Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)

ABSTRACT

Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives of formula I are provided:  
                 
 
     wherein: R 1 , R 2,  R 3,  R 4  and R 5  are as defined herein which are useful as inhibitors of plasminogen activator inhibitor-1 (PAI-1) for treating conditions resulting from fibrinolytic disorders, such as deep vein thrombosis and coronary heart disease, and pulmonary fibrosis.

[0001] This application claims priority from co-pending provisionalapplication serial No. 60/432,107 filed on Dec. 10, 2002, the entiredisclosure of which is hereby incorporated by reference.

[0002] This invention relates to substituted 3-carbonyl-1H-indol-1-ylacetic acid derivatives as inhibitors of plasminogen activatorinhibitor-1 (PAI-1) and as therapeutic compositions for treatingconditions resulting from fibrinolytic disorders such as deep veinthrombosis and coronary heart disease, and pulmonary fibrosis.

BACKGROUND OF INVENTION

[0003] Plasminogen activator inhibitor-1 (PAI-1) is a major regulatorycomponent of the plasminogen-plasmin system. PAI-1 is the principalphysiologic inhibitor of both tissue type plasminogen activator (tPA)and urokinase type plasminogen activator (uPA). Elevated plasma levelsof PAI-1 have been associated with thrombotic events as indicated byanimal experiments (Krishnamurti, Blood, 69, 798 (1987); Reilly,Arteriosclerosis and Thrombosis, 11, 1276 (1991); Carmeliet, Journal ofClinical Investigations, 92, 2756 (1993)) and clinical studies (Rocha,Fibrinolysis, 8, 294, 1994; Aznar, Haemostasis 24, 243 (1994)). Antibodyneutralization of PAI-1 activity resulted in promotion of endogenousthrombolysis and reperfusion (Biemond, Circulation, 91, 1175 (1995);Levi, Circulation 85, 305, (1992)). Elevated levels of PAI-1 have alsobeen implicated in diseases of women such as polycystic ovary syndrome(Nordt, Journal of Clinical Endocrinology and Metabolism, 85, 4, 1563(2000)) and bone loss induced by estrogen deficiency (Daci, Journal ofBone and Mineral Research, 15, 8, 1510 (2000)). Accordingly, agents thatinhibit PAI-1 would be of utility in treating conditions originatingfrom fibrinolytic disorder such as deep vein thrombosis, coronary heartdisease, pulmonary fibrosis, polycystic ovary syndrome, etc.

[0004] WO 99/43654 and WO 99/43651 describe indole derivatives offormula I as inhibitors of phospholipase enzymes useful in preventinginflammatory conditions:

[0005] WO 2000/44743 discloses TGF-β production inhibitors of formula I:

[0006] where R₁ and R₂ are each independently hydrogen, optionallysubstituted alkyl, acyl, optionally substituted aryl or aromaticheterocyclic group and

[0007] R₇ is an optionally substituted cyclic amino orazabicycloalkylamino.

[0008] WO 97/48697 describes substituted azabicyclic compounds inclusiveof indoles, 2,3-dihydro-1H-indoles, and benzimidazoles of formula (I)for the treatment of conditions ameliorated by the administration of aninhibitor of tumor necrosis factor:

[0009] where A is a five-membered aza heterocycle;

[0010] B is a six membered aza heterocycle or an optionally substitutedbenzene ring;

[0011] Z₁ is a chemical bond, O, S, or NH;

[0012] A₁ is a chemical bond, alkyl of 1-6 carbons, alkenylene of 2-6carbons, or alkynylene of 2-6 carbons;

[0013] R₁ is hydrogen or optionally substituted alkyl of 2-6 carbons,lower alkenyl or lower alkynyl;

[0014] R₂ is hydrogen, alkenyl, alkyl, alkylsulfinyl, alkylsulphonyl,alkylthio, aryl, arylalkoxy, arylalkylsulphinyl, arylalkylsulphonyl,arylalkylthio, aryloxy, arylsulphinyl, arylsulphonyl, arylthio, —CN,cycloalkenyl, cycloalkenoxy, cycloalkyl, cycloalkyloxy, heteroaryl,heteroarylalkyloxy, heteroaryloxy, —OH, —SO₂NR₄R₅, —NR₄SO₂R₅, —NR₄R₅,—C(O)R₅, —C(O)C(O)R₅, —O(C═O)NR₄R₅, —C(O)OR₅, or —O(C═O)NR₄R₅, and

[0015] R₃ is carboxamide, acyl, substituted alkenyl, substituted alkyl,acylamino, oximino, alkynyl, ketomethyl, aminoalkyl, sulfonylmethyl,sulfinylmethyl, CF₂OR, alkylamino, alkoxy, alkylsulfanyl, sulfinyl,acyloxy, sulfonyl, OCF₂R, azo, aminosulfonyl, sulfonylamino, oraminooxalyl.

[0016] U.S. Pat. No. 5,612,360 describes tetrazolylphenyl-substitutedheterocycles of formula (I) as angiotensin II inhibitors.

[0017] where: R₁ is —COOH, —S(O)₃H, —PO₃H₂, —C(O)NHSO₂R₈, or5-tetrazolyl;

[0018] R₂ is hydrogen, —OH, —OAc, halogen, alkyl of 1-4 carbons, oralkoxy of 1-4 carbons;

[0019] R₃ is substituted benzimidazole, indazole, or

[0020] R₄ is:

[0021] R₆ may be (CH₂)_(p)R₁, CONH(C₁ to C₄ alkyl), or CONH(C₁ to C₄trifluoroalkyl) where p is 0, 1, 2, 3 or 4.

[0022] R₇ is alkyl, trifluoroalkyl, alkenyl, or trifluoroalkenyl all of4-9 carbons;

[0023] R₁₁ is hydrogen, alkyl of 1-4 carbons, halogen, or(CH₂)_(n)phenyl; X is —(CH₂)_(m)CONH—, —(CH₂)_(m)NHCO—, —CH₂—, —O—,—NH—, or —(CH₂)_(m)CO—; and m is O or 1, where m is 0 or 1 and n is 1, 2or 3.

[0024] FR 2,054,450 describes carboxymethyl indoles of formula (I) asanti-inflammatory agents:

[0025] where: A is linear alkyl;

[0026] X is phenyl, optionally substituted with chlorine, alkyloxy,alkylthio, or alkylsulfonyl;

[0027] Y is alkyl; and

[0028] Z is hydrogen or alkyloxy.

SUMMARY OF THE INVENTION

[0029] This invention relates to compounds of formula (I):

[0030] wherein:

[0031] R₁ is hydrogen, C₂-C₆ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆cycloalkyl, or C₁-C₃ perfluoroalkyl, wherein the alkyl and cycloalkylgroups may be optionally substituted with halogen, —CN, C₁-C₆ alkoxy,—OH, —NH₂, or —NO₂;

[0032] R₂ is hydrogen, C₁-C₈ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆cycloalkyl, thienyl, CH₂-thienyl, furanyl, CH₂-furanyl, oxazoyl,CH₂-oxazoyl, phenyl, benzyl, CH₂-naphthyl, wherein the alkyl group andrings of the cycloalkyl, thienyl, furanyl, oxazoyl, phenyl, benzyl, andnapthyl groups may be optionally substituted with from 1 to 3 groupsselected from halogen, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, O—C₁-C₃perfluoroalkyl, S—C₁-C₃ perfluoroalkyl, C₁-C₃ alkoxy, —OCHF₂, —CN,—COOH, —CH₂CO₂H, —C(O)CH₃, —CO₂R₆, —C(O)NH₂, —S(O)₂CH₃, —OH, —NH₂, or—NO₂;

[0033] R₃ is hydrogen, halogen, C₁-C₆ alkyl, C₁-C₃ perfluoroalkyl,preferably —CF₃, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl,—NH₂, or —NO₂;

[0034] R₄ is C₃-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆cycloalkyl, —CH₂—C₃-C₆ cycloalkyl, thienyl, furanyl, oxazoyl, phenyl,benzo[b]furan-2-yl, benzo[b]thien-2-yl, benzo[1,3]dioxol-5-yl, naphthyl,wherein the alkyl group and the rings of the cycloalkyl, thienyl,furanyl, oxazoyl, phenyl, benzofuranyl, benzothienyl, and naphthylgroups may be optionally substituted by from 1 to 3 groups selected fromhalogen, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, O—C₁-C₃ perfluoroalkyl,S—C₁-C₃ perfluoroalkyl, C₁-C₃ alkoxy, —OCHF₂, —CN, —COOH, CH₂CO₂H,—C(O)CH₃, —C(O)OR₆, —C(O)NH₂, —S(O)—₂CH₃, —OH, —NH₂, or —NO₂;

[0035] R₅ is C₁-C₈ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl,pyridinyl, —CH₂-pyridinyl, thienyl, CH₂-thienyl, furanyl, CH₂-furanyl,oxazoyl, CH₂-oxazoyl, phenyl, benzyl, benzo[b]furan-2-yl,benzo[b]thien-2-yl, benzo[1,3]dioxol-5-yl, naphthyl, CH₂-naphyl,9H-fluoren-1-yl, 9H-fluoren-4-yl, 9H-fluoren-9-yl, 9-fluorenone-1-yl,9-fluorenone-2-yl, 9-fluorenone-4-yl, CH₂-9H-fluoren-9-yl, wherein thealkyl group and the rings of the cycloalkyl, pyridinyl, thienyl,furanyl, oxazoyl, phenyl, benzyl, benzofuranyl, benzothienyl, napthyl,fluorenyl, and fluorenone groups may be optionally substituted by from 1to 3 groups selected from halogen, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, C₁-C₃perfluoroalkyl, —O—C₁-C₃ perfluoroalkyl, —S—C₁-C₃ perfluoroalkyl, C₁-C₃alkoxy, phenoxy, —OCHF₂, —CN, —COOH, —CH₂CO₂H, —C(O)CH₃, —CO₂R₆,—C(O)NH₂, —S(O)₂CH₃, —OH, —NH₂, or —NO₂, wherein the phenoxy group maybe optionally substituted by from 1 to 3 groups selected from halogen,C₁-C₃ alkyl, or C₁-C₃ perfluoroalkyl; and

[0036] R₆ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl, orbenzyl;

[0037] or a pharmaceutically acceptable salt or ester form thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0038] Preferred compounds of the present invention are those of formula(I) wherein R₁-R₃ and R₅-R₆ are as defined above, and

[0039] R₄ is thienyl, furanyl, oxazoyl, phenyl, benzo[b]furan-2-yl,benzo[b]thien-2-yl, benzo[1,3]dioxol-5-yl or naphthyl, wherein the ringsof the thienyl, furanyl, oxazoyl, phenyl, benzofuranyl, benzothienyl,and napthyl groups may be optionally substituted by from 1 to 3 groupsselected from halogen, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, —O—C₁-C₃perfluoroalkyl, —S—C₁-C₃ perfluoroalkyl, C₁-C₃ alkoxy, —OCHF₂, —CN,—COOH, —CH₂CO₂H, —C(O)CH₃, —CO₂R₆, —C(O)NH₂, —S(O)₂CH₃, —OH, —NH₂, or—NO₂;

[0040] or a pharmaceutically acceptable salt or ester form thereof.

[0041] Specific compounds according to this invention include:

[0042] [3-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1H-indol-1yl]acetic acid;

[0043][3-(benzo[b]thiophene-2-carbonyl)-5-(4-methylphenyl)-1H-indol-1-yl]aceticacid; and

[0044] [3-(4-chlorobenzoyl)-5-(4-methylphenyl)-1H-indol-1yl]acetic acid,or a pharmaceutically acceptable salt or ester form thereof.

[0045] The preferred salt forms of the compounds herein include but arenot limited to sodium salts, and potassium salts. Other useful saltforms of these compounds include those formed with pharmaceuticallyacceptable inorganic and organic bases known in the art. Salt formsprepared using inorganic bases include hydroxides, carbonates orbicarbonates of the therapeutically acceptable alkali metals or alkalineearth methals, such as sodium potassium, magnesium, calcium and thelike. Acceptable organic bases include amines, such as benzylzmine,mono-, di- and trialkylamines, preferably those having alkyl groups offrom 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms, such asmethylamine, dimethylamine, trimethylamine, ethylamine, diethylamine,triethylamine, mono-, di-, and triethanolamine. Also useful are alkylenediamines containing up to 6 carbon atoms, such as hexamethylenediamine;cyclic saturated or unsaturated bases containing up to 6 carbon atoms,including pyrrolidine, peperidine, morpholine, piperazine and theirN-alkyl and N-hydroxyalkyl derivatives, such as N-methyl-morpholine andN-(2-hyroxyethyl)-piperidine, or pyridine. Quaternary salts may also beformed, such as tetralkyl forms, such as tetramethyl forms,alkyl-alkanol forms, such as methyl-triethanol or trimethyl-monoethanolforms, and cyclic ammonium salt forms, such as N-methylpyridinium,N-methyl-N-(2-hydroxyethyl)-morpholinium, N,N-di-methylmorpholinium,N-mehtyl-N-(2-hydroxyethyl)-morpholinium, or N,N-dimethyl-piperidiniumsalt forms. These salt forms may be prepared using the acidiccompound(s) of Formula I and procedures known in the art.

[0046] Ester forms of the compounds of this invention include straightchain alkyl esters having from 1 to 6 carbon atoms or branched chainalkyl groups containing 3 or 6 carbon atoms, including methyl, ethyl,propyl, butyl, 2-methylpropyl and 1,1-dimethylethyl esters. Other estersuseful with this invention include those of the formula —COOR₇ whereinR₇ is selected from the formulae:

[0047] wherein R₈, R₉, R₁₀, R₁₁ are independently selected fromhydrogen, alkyl of from 1 to 10 carbon atoms, aryl of 6 to 12 carbonatoms, arylalkyl of from 6 to 12 carbon atoms; heteroaryl oralkylheteroaryl wherein the heteroaryl ring is bound by an alkyl chainof from 1 to 6 carbon atoms.

[0048] Among the preferred ester forms of the compounds herein includebut not limited to C₁-C₆ alkyl esters, C₃-C₆ branched alkyl esters,benzyl esters, etc.

[0049] As used herein, the terms alkyl, alkenyl and alkynyl include bothstraight chain as well as branched claim chains. Preferably, the C₁-C₃perfluoroalkyl substituent is —CF₃; the —O—C₁-C₃ perfluoroalkylsubstituent is OCF₃; and the —S—C—C₃ perfluoroalkyl substituent is—SCF₃.

[0050] As used herein, “aryl” refers to an unsaturated aromaticcarbocyclic group of from 6 to 14 carbon atoms having a single ring(e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl oranthryl). Preferred aryl groups include phenyl, naphthyl and the like.As used herein, “heteroaryl” refers to a monocyclic or bicyclic aromaticgroup of from 1 to carbon atoms and 1 to 4 heteroatoms selected fromoxygen, nitrogen and sulfur within at least one ring (if there is morethan one ring). Such heteroaryl groups can have a single ring, such aspyridyl, pyrrolyl or furyl groups, or multiple condensed rings, such asindolyl, indolizinyl, benzofuranyl or benzothienyl groups. Preferredheteroaryls include pyridyl, pyrrolyl and furyl.

[0051] Unless otherwise limited by the definition for the aryl orheteroaryl groups herein, such groups can optionally be substituted withfrom 1 to 5 substituents selected from the group consisting of acyloxy,hydroxy, acyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbonatoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms,substituted alkyl, substituted alkoxy, substituted alkenyl, substitutedalkynyl, amino, amino substituted by one or two alkyl groups of from 1to 6 carbon atoms, aminoacyl, acylamino, azido, cyano, halo, nitro,thioalkoxy of from 1 to 6 carbon atoms, substituted thioalkoxy of from 1to 6 carbon atoms, and trihalomethyl. Substituents on the alkyl,alkenyl, alkynyl, thioalkoxy and alkoxy groups mentioned above includehalogens, CN, OH, and amino groups. Preferred substituents on the arylgroups herein include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl,and thioalkoxy.

[0052] The compounds of the present invention are inhibitors of theserine protease inhibitor PAI-1, and are therefore useful in thetreatment, inhibition, prevention or prophylaxis in a mammal, preferablyin a human, of those processes which involve the production and/oraction of PAI-1. Thus, the compounds of the invention are useful in thetreatment or prevention of noninsulin dependent diabetes mellitus andcardiovascular disease caused by such condition, and prevention ofthrombotic events associated with coronary artery and cerebrovasculardisease. These compounds are also useful for inhibiting the diseaseprocess involving the thrombotic and prothrombotic states which include,but are not limited to, formation of atherosclerotic plaques, venous andarterial thrombosis, myocardial ischemia, atrial fibrillation, deep veinthrombosis, coagulation syndromes, pulmonary fibrosis, cerebralthrombosis, thromboembolic complications of surgery (such as jointreplacement), and peripheral arterial occlusion. These compounds arealso useful in treating stroke associated with or resulting from atrialfibrillation.

[0053] The compounds of the invention may also be used in the treatmentof diseases associated with extracellular matrix accumulation,including, but not limited to, renal fibrosis, chronic obstructivepulmonary disease, polycystic ovary syndrome, restenosis, renovasculardisease and organ transplant rejection.

[0054] The compounds of the invention may also be used in the treatmentof malignancies, and diseases associated with neoangiogenesis (such asdiabetic retinopathy).

[0055] The compounds in the invention may also be used in conjunctionwith and following processes or procedures involving maintaining bloodvessel patency, including vascular surgery, vascular graft and stentpatency, organ, tissue and cell implantation and transplantation.

[0056] The compounds in the invention may also be useful in thetreatment of inflammatory diseases, septic shock and the vascular damageassociated with infections.

[0057] The compounds of the invention are useful for the treatment ofblood and blood products used in dialysis, blood storage in the fluidphase, especially ex vivo platelet aggregation. The present compoundsmay also be added to human plasma during the analysis of blood chemistryin hospital settings to determine the fibrinolytic capacity thereof.

[0058] The compounds in the present invention may also be used incombination with prothrombolytic, fibrinolytic and anticoagulant agents.

[0059] The compounds of the present invention may also be used to treatcancer including, but not limited to, breast and ovarian cancer, and asimaging agents for the identification of metastatic cancers.

[0060] The compounds of the invention may also be used in the treatmentof Alzheimer's disease. This method may also be characterized as theinhibition of plasminogen activator by PAI-1 in a mammal, particularly ahuman, experiencing or subject to Alzhemier's disease. This method mayalso be characterized as a method of increasing or normalizing levels ofplasmin concentration in a mammal, particularly those experiencing orsubject to Alzheimer's disease.

[0061] The compounds of the invention may be used for the treatment ofmyelofibrosis with myeloid metaplasia by regulating stromal cellhyperplasia and increases in extracellular matrix proteins.

[0062] The compounds of the invention may also be used in conjunctionwith protease inhibitor—containing highly active antiretroviral therapy(HAART) for the treatment of diseases which originate from fibrinolyticimpairment and hyper-coagulability of HIV-1 infected patients receivingsuch therapy.

[0063] The compounds of the invention may be used for the treatment ofdiabetic nephropathy and renal dialysis associated with nephropathy.

[0064] The compounds of the invention may be used to treat cancer,septicemia, obesity, insulin resistance, proliferative diseases such aspsoriasis, improving coagulation homeostasis, cerebrovascular diseases,microvascular disease, hypertension, dementia, osteoporosis, arthritis,asthma, heart failure, arrhythmia, angina, and as a hormone replacementagent, treating, preventing or reversing progression of atherosclerosis,Alzheimer's disease, osteoporosis, osteopenia; reducing inflammatorymarkers, reducing C-reactive protein, or preventing or treating lowgrade vascular inflammation, stroke, dementia, coronary heart disease,primary and secondary prevention of myocardial infarction, stable andunstable angina, primary prevention of coronary events, secondaryprevention of cardiovascular events, peripheral vascular disease,peripheral arterial disease, acute vascular syndromes, reducing the riskof undergoing a myocardial revascularization procedure, microvasculardiseases such as nephropathy, neuropathy, retinopathy and nephroticsyndrome, hypertension, Type I and 2 diabetes and related diseases,hyperglycemia, hyperinsulinemia, malignant lesions, premalignantlesions, gastrointestinal malignancies, liposarcomas and epithelialtumors, proliferative diseases such as psoriasis, improving coagulationhomeostasis, and/or improving endothelial function, and all forms ofcerebrovascular diseases.

[0065] The compounds of the invention may be used for the topicalapplications in wound healing for prevention of scarring.

[0066] Methods for the treatment, inhibition, prevention or prophylaxisin a mammal of each of the conditions or maladies listed herein are partof the present invention. Each method comprises administering to amammal in need thereof a pharmaceutically or therapeutically effectiveamount of a compound of this invention, or a pharmaceutically acceptablesalt or ester form thereof.

[0067] Each of the methods described herein comprise administering to amammal in need of such treatment a pharmaceutically effective amount ofa compound of this invention, or a pharmaceutically acceptable salt orester form thereof. It will be understood that a pharmaceuticallyeffective amount of the compound will be at least the minimum amountnecessary to provide an improvement in the symptoms or underlyingcausation of the malady in question or to inhibit or lessen the onset ofsymptoms of the malady.

[0068] Accordingly the present invention further comprises a method ofinhibiting in a mammal plasminogen activator inhibitor type 1 (PAI-1)which comprises administering to a mammal in need thereof apharmaceutically effective amount of a compound of Formula (I):

[0069] wherein,

[0070] R₁ is hydrogen, C₂-C₆ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆cycloalkyl, or C₁-C₃ perfluoroalkyl, wherein the alkyl and cycloalkylgroups may be optionally substituted with halogen, —CN, C₁-C₆ alkoxy,—OH, —NH₂, or —NO₂;

[0071] R₂ is hydrogen, C₁-C₈ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆cycloalkyl, thienyl, CH₂-thienyl, furanyl, CH₂-furanyl, oxazoyl,CH₂-oxazoyl, phenyl, benzyl, CH₂-naphthyl, wherein the alkyl group andrings of the cycloalkyl, thienyl, furanyl, oxazoyl, phenyl, benzyl, andnapthyl groups may be optionally substituted with from 1 to 3 groupsselected from halogen, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, O—C₁-C₃perfluoroalkyl, S—C₁-C₃ perfluoroalkyl, C₁-C₃ alkoxy, —OCHF₂, —CN,—COOH, —CH₂CO₂H, —C(O)CH₃, —CO₂R₆, —C(O)NH₂, —S(O)₂CH₃, —OH, —NH₂, or—NO₂;

[0072] R₃ is hydrogen, halogen, C₁-C₆ alkyl, C₁-C₃ perfluoroalkyl,preferably —CF₃, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl,—NH₂, or —NO₂;

[0073] R₄ is C₃-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆cycloalkyl, —CH₂—C₃-C₆ cycloalkyl, thienyl, furanyl, oxazoyl, phenyl,benzo[b]furan-2-yl, benzo[b]thien-2-yl, benzo[1,3]dioxol-5-yl, naphthyl,wherein the alkyl group and the rings of the cycloalkyl, thienyl,furanyl, oxazoyl, phenyl, benzofuranyl, benzothienyl, and napthyl groupsmay be optionally substituted by from 1 to 3 groups selected fromhalogen, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, O—C₁-C₃ perfluoroalkyl,S—C₁-C₃ perfluoroalkyl, C₁-C₃ alkoxy, —OCHF₂, —CN, COOH, —CH₂CO₂H,—C(O)CH₃, —C(O)OR₆, —C(O)NH₂, —S(O)—₂CH₃, —OH, —NH₂, or —NO₂;

[0074] R₅ is C₁-C₈ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl,pyridinyl, —CH₂-pyridinyl, thienyl, CH₂-thienyl, furanyl, CH₂-furanyl,oxazoyl, CH₂-oxazoyl, phenyl, benzyl, benzo[b]furan-2-yl,benzo[b]thien-2-yl, benzo[1,3]dioxol-5-yl, naphthyl, CH₂-naphthyl,9H-fluoren-1-yl, 9H-fluoren-4-yl, 9H-fluoren-9-yl, 9-fluorenone-1-yl,9-fluorenone-2-yl, 9-fluorenone-4-yl, CH₂-9H-fluoren-9-yl, wherein thealkyl group and the rings of the cycloalkyl, pyridinyl, thienyl,furanyl, oxazoyl, phenyl, benzyl, benzofuranyl, benzothienyl, naphthyl,fluorenyl, and fluorenone groups may be optionally substituted by from 1to 3 groups selected from halogen, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, C₁-C₃perfluoroalkyl, —O—C₁-C₃ perfluoroalkyl, —S—C₁-C₃ perfluoroalkyl, C₁-C₃alkoxy, phenoxy, —OCHF₂, —CN, —COOH, —CH₂CO₂H, —C(O)CH₃, —CO₂R₆,—C(O)NH₂, —S(O)₂CH₃, —OH, —NH₂, or —NO₂, wherein the phenoxy group maybe optionally substituted by from 1 to 3 groups selected from halogen,C₁-C₃ alkyl, or C₁-C₃ perfluoroalkyl; and

[0075] R₆ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl, orbenzyl;

[0076] or a pharmaceutically acceptable salt or ester form thereof.

Process of the Invention

[0077] The compounds of the present invention can be readily preparedaccording to the following reaction scheme or modification thereof aswould be recognized by one skilled in the art using readily availablestarting materials, reagents and conventional synthetic procedures. Itis also possible to make use of variants of these process steps, whichin themselves are known to and well within the preparatory skill of themedicinal chemist. In the following reaction schemes, R₁-R₆ are selectedfrom the groups defined above. R₁₂ and R₁₃ are each independentlyhydrogen, halogen, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, preferably —CF₃,—O—C₁-C₃ perfluoroalkyl, preferably —OCF₃, —S—C₁-C₃ perfluoroalkyl,preferably —SCF₃, C₁-C₃ alkoxy, —OCHF₂, —C(O)CH₃, —C(O)NH₂, —S(O)₂CH₃,—OH, —NH₂, or —NO₂;

[0078] Method A

[0079] In Method A, indole, substituted on the benzene ring withbromide, iodine, or triflate, is cross-coupled with an aryl boronic acidin the presence of a palladium catalyst, such as Pd(PPh₃)₄, a base, suchas Na₂CO₃ or NaHCO₃, in a solvent, such as water, dioxane, THF, toluene,methanol or ethanol, or in a mixed co-solvent system comprising two ormore of the aforesaid solvents, at 50-110° C. Boronic acid derivativesof benzene, furan, thiophene, benz[b]thiophene and napthylene aredescribed in the literature and many are presently commerciallyavailable. The resulting aryl substituted indole may be alkylated onnitrogen using methyl bromoacetate in the presence of a base, such asNaH or KOt-Bu, in an inert solvent, such as THF or DMF. The resultingaryl indo-1-yl acetic acid methyl ester is acylated at the C-3 positionby an acid chloride in a solvent, such as dichloromethane (DCM) ordichloroethane (DCE), in the presence of a Lewis acid, such as SnCl₄ at−40 to +25° C. The methyl ester may be hydrolyzed with base and purifiedby chromatography or by HPLC to afford the 1H-indol-1-yl acetic acidcompounds.

[0080] Method B

[0081] Indoles containing alkyl, alkenyl and alkynyl substituents mayalso be prepared from indole substituted on the benzene ring withbromide, iodine, or triflate via palladium catalyzed coupling reactionwith primary acetylenes. This reaction can be performed using apalladium catalyst, such as Pd(PPh₃)₄, a base, such as HN(i-Pr)₂ orEtN(i-Pr)₂, with or without a copper salt, such as CuI or CuBr, in aninert solvent, such as MeCN or toluene. The resulting alkynylindoles maybe reduced to alkenyl- or alkylindoles by catalytic hydrogenation.Indoles substituted with alkyl, cycloalkyl, and benzyl groups can beprepared from the same substituted indoles by a nickle catalyzedcoupling reaction. This reaction uses an alkylmagnesium couplingpartner, such as C₆H₁₁CH₂MgCl, PhCH₂MgCl, or PhCMe₂CH₂MgCl and a nicklecatalyst, such as Ni(dppf)Cl₂(dppf=1,1′-bis(diphenylphosphino)ferrocene) to give the correspondingsubstituted indoles. These indoles can then be further elaborated asdescribed in Method A to give the desired indol-1-yl acetic acids.

[0082] This invention also provides pharmaceutical compositionscomprising substituted 1H-indol-1-yl acetic acid derivatives of FormulaI as described herein either alone or in combination with excipients(i.e. pharmaceutically acceptable materials with no pharmacologicaleffects and pharmaceutically acceptable carriers). A pharmaceutically ortherapeutically effective amount of a compound of this invention refersto an amount of the compound which will sufficiently inhibit the severeprotease inhibitor PAI-I in a mammal in need thereof to providesufficient inhibition of PAI-I.

[0083] The precise dosage to be employed depends upon several factorsincluding the host, whether in veterinary medicine or human medicine,the nature and severity of the condition being treated, the mode ofadministration and the particular active substance employed. Thecompounds may be administered by any conventional route, in particularenterally, preferably orally in the form of tablets or capsules.Administered compounds can be in the free form or pharmaceuticallyacceptable salt form as appropriate, for use as a pharmaceutical,particularly for use in the prophylactic or curative treatment ofatherosclerosis and sequelae (angina pectoris, myocardial infarction,arrhythmias, heart failure, kidney failure, stroke, peripheral arterialocclusion, and related disease states). These measures will slow therate of progress of the disease state and assist the body in reversingthe process direction in a natural manner.

[0084] Any suitable carrier known to the art can be used to prepare thepharmaceutical compositions. In such a composition, the carrier may be asolid, liquid or mixture of a solid and a liquid. Solid compositionsinclude powders, tablets and capsules. A solid carrier can be one ormore substances which may also act as a flavoring agent, lubricant,solubilizer, suspending agent, binder, or tablet disintegrant. Inpowders, the carrier is a finely divided solid, which is in admixturewith the finely divided active ingredient. In tablets, the activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired. Suitable solid carriers are magnesium carbonate, magnesiumstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methyl cellulose, hydroxymethyl cellulose, sodiumcarboxymethyl cellulose, a low melting wax, cocoa butter, and the like.Encapsulating materials may also be employed with the compounds of thisinvention, and the term “composition” is intended to include the activeingredient in combination with an encapsulating material as aformulation, with or without other carriers. Cachets may also be used inthe delivery of the anti-atherosclerotic medicament of this invention.

[0085] Sterile liquid compositions include solutions, suspensions,emulsions, syrups and elixirs. The compounds of this invention may bedissolved or suspended in the pharmaceutically acceptable carrier, suchas sterile water, sterile organic solvent or a mixture of both.Preferably the liquid carrier is one suitable for parental injection.Where the compounds are sufficiently soluble they can be dissolveddirectly in normal saline with or without the use of suitable organicsolvents, such as propylene glycol or polyethylene glycol. If desired,dispersions of the finely divided compounds can be made-up in aqueousstarch or sodium carboxymethyl cellulose solution, or in a suitable oil,such as arachis oil. Liquid pharmaceutical compositions, which aresterile solutions or suspensions, can be utilized by intramuscular,intraperitoneal or subcutaneous injection. In many instances a liquidcomposition form may be used instead of the preferred solid oral methodof administration.

[0086] It is preferred to prepare unit dosage forms of the compounds forstandard administration regimens. In this way, the composition can besubdivided readily into smaller doses at the physicians direction. Forexample, unit dosages may be made up in packeted powders, vials orampoules and preferably in capsule or tablet form. The active compoundpresent in these unit dosage forms of the composition may be present inan amount of from about one gram to about fifteen grams or more, forsingle or multiple daily administration, according to the particularneed of the patient. The daily dose of active compound will varydepending upon the route of administration, the size, age and sex of thepatient, the severity of the disease state, and the response to thetherapy as traced by blood analysis and the patients recovery rate. Byinitiating the treatment regimen with a minimal daily dose of about onegram, the blood levels of PAI-1 and the patients symptomatic reliefanalysis may be used to determine whether a larger dose is indicated.Based upon the data presented below, the projected daily dose for bothhuman and veterinary use will be from about 25 to about 200milligrams/kilogram per day, and more usually, from about 50 to about100 milligrams/kilogram per day.

[0087] The ability of the compounds of this invention to inhibitplasminogen activator inhibitor-1 was established by the followingexperimental procedures:

Primary Screen for the PAI-1 Inhibition

[0088] Test compounds were dissolved in DMSO at a final concentration of10 mM, then diluted 100× in physiologic buffer. The inhibitory assay wasinitiated by the addition of the test compound (1-100 μM finalconcentration, maximum DMSO concentration of 0.2%) in a pH 6.6 buffercontaining 140 nM recombinant human plasminogen activator inhibitor-1(Molecular Innovations, Royal Oak, Mich.). Following a 1 hour incubationat room temperature, 70 nM of recombinant human tissue plasminogenactivator (tPA) was added, and the combination of the test compound,PAI-1 and tPA was incubated for an additional 30 minutes. Following thesecond incubation, Spectrozyme-tPA (American Diagnostica, Greenwich,Conn.), a chromogenic substrate for tPA, was added and absorbance wasread at 405 nm at 0 and 60 minutes. Relative PAI-1 inhibition was equalto the residual tPA activity in the presence of the test compound andPAI-1. Control treatments included the complete inhibition of tPA byPAI-1 at the molar ratio employed (2:1), and the absence of any effectof the test compound on tPA alone.

Assay for Determining IC₅₀ of Inhibition of PAI-1

[0089] This assay was based upon the non-SDS dissociable interactionbetween tPA and active PAI-1. Assay plates were initially coated withhuman tPA (10 μg/ml). The test compounds were dissolved in DMSO at 10mM, then diluted with physiologic buffer (pH 7.5) to a finalconcentration of 1-50 μM. The test compounds were incubated with humanPAI-1 (50 ng/ml) for 15 minutes at room temperature. The tPA-coatedplate was washed with a solution of 0.05% Tween 20 and 0.1% BSA, thenthe plate was blocked with a solution of 3% BSA. An aliquot of the testcompound/PAI-1 solution was then added to the tPA-coated plate,incubated at room temperature for 1 hour and washed. Active PAI-1 boundto the plate was assessed by adding an aliquot of a 1:1000 dilution ofthe 33B8 monoclonal antibody against human PAI-1, and the plate wasincubated at room temperature for 1 hour (Molecular Innovations, RoyalOak, Mich.). The plate was again washed, and a solution of goatanti-mouse IgG-alkaline phosphatase conjugate was added at a 1:50,000dilution in goat serum. The plate was incubated 30 minutes at roomtemperature, washed, and a solution of alkaline phosphatase substratewas added. The plate was incubated 45 minutes at room temperature, andcolor development was determined at OD_(405nm). The quantitation ofactive PAI-1 bound to tPA at varying concentrations of test compound wasused to determine the IC₅₀. Results were analyzed using a logarithmicbest-fit equation. The assay sensitivity was 5 ng/ml of human PAI-1 asdetermined from a standard curve ranging from 0-100 ng/ml.

[0090] The compounds of the present invention inhibited PlasminogenActivator Inhibitor-1 as summarized in Table I. TABLE 1 Inhibition ofPlasminogen Activator Inhibitor-1 by Examples 1-3 % Inhibition Example @25 uM 1 47 2 45 3 46

EXAMPLE 1

[0091] [3-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1H-indol-1-yl]acetic Acid

[0092] Step 1:

[0093] A stirred slurry of 6.35 g (60 mmol) K₂CO₃, 2.94 g (15 mmol)5-bromoindole, 2.50 g (16 mmol) 4-chlorophenylboronic acid, and 0.48 g(0.42 mmol) tetrakistriphenylphosphine palladium was heated to refluxfor 2½ hours. The reaction mixture was allowed to cool and was thenpoured into 200 ml water and extracted with EtOAc. The organic layer wasseparated, dried over MgSO₄, and concentrated. The residue waschromatographed on silica to afford 1.39 g 5-(4-chlorophenyl)indole as awhite solid.

[0094] Step 2:

[0095] To a solution of 0.68 g (3.0 mmol) 5-(4-chlorophenyl)indole in 20ml anhydrous DMF was added 3.1 ml 1.0 M solution of KOt-Bu in THF. Thesolution was stirred at room temperature for 15 min and then 0.29 ml(3.1 mmol) methyl bromoacetate was added. The solution was stirred atroom temperature overnight. The solution was concentrated under vacuumand the residue was dissolved in a minimal amount of EtOAc. Thissolution was washed once with water and the organic phase was decantedfrom the aqueous phase with a pipet and loaded directly on a column ofsilica where it was chromatographed using 15-25% EtOAc-hexane. Thisafforded 0.485 g [5-(4-chloro-phenyl)-indol-1-yl]-acetic acid methylester as a solid.

[0096] Step 3:

[0097] To a solution of 0.485 g (1.61 mmol) product from Step 2 and 0.24ml (1.9 mmol) 4-chlorobenzoyl chloride in 10 ml dichloroethane, cooledto 0° C. in ice, was added 1.9 ml 1.0 M solution SnCl₄ in DCM. The icebath was removed and the reaction allowed to stir at room temperatureovernight. The solution was poured into saturated aqueous NaHCO₃ withstirring and the solution was extracted with EtOAc. The organic phasewas dried over MgSO₄ and concentrated. The residue was chromatographedon silica using 20-40% EtOAc-hexane to afford a solid which wastriturated from diethyl ether to afford 0.30 g[3-(4-chloro-benzoyl)-5-(4-chloro-phenyl)-indol-1-yl]-acetic acid methylester as colorless crystals.

[0098] Step 4:

[0099] To a solution of 0.30 g (0.68 mmol) product from Step 3 in 5 mlTHF was added a solution of 0.11 g (2.72 mmol) lithium hydroxide hydratein 5 ml water. The solution was stirred at room temperature overnight,acidified with 4 ml 1 N aqueous HCL, diluted with water, and extractedonce each with dichloromethane and EtOAc. The combined organic extractswere concentrated and the residue was purified by RP-HPLC to afford0.106 g Example 1: mp 255-257° C.; ¹H NMR (DMSO-d₆, 300 MHz) δ 5.20 (s,2H), 7.54 (d, J=8.4 Hz, 2H), 7.58-7.71 (m, 4H), 7.72 (d, J=8.7 Hz, 2H)7.82 (d, J=8.4 Hz, 2H), 8.16 (s, 1H), 8.52 (s, 1H); MS: m/z (ESI) 422(M−H); Anal. calcd for (C₂₃H₁₅Cl₂NO₃) C, H, N.

[0100] The compounds of Examples 2 and 3 were prepared by the methodused to prepare the compound of Example I, using 5-bromoindole,4-methylbenzeneboronic acid, benzo[b]thiophene-2-carbonyl chloride, and4-chlorobenzoyl chloride and purified by semi-preparative RP-HPLC¹.

EXAMPLE 2

[0101][3-(Benzo[b]thiophene-2-carbonyl)-5-(4-methylphenyl)-1H-indol-1-yl]-aceticAcid

[0102] MS: m/z (ESI) 426 (M+H); LCMS² retention time: 2.15 min.

EXAMPLE 3

[0103] [3-(4-chlorobenzoyl)-5-(4-methylphenyl)-1H-indol-1-yl]-aceticAcid

[0104] MS: m/z (ESI) 426 (M+H); LCMS² retention time: 1.85 min.

[0105] Notes:

[0106] 1. Semi-Preparative RP-HPLC Conditions:

[0107] Gilson Semi-Preparative HPLC system with Unipoint Software

[0108] Column: Phenomenex C18 Luna 21.6 mm×60 mm, 5 μM; Solvent A: Water(0.02% TFA buffer); Solvent B: Acetonitrile (0.02% TFA buffer); SolventGradient: Time 0: 5% B; 2.5 min: 5% B; 7 min: 95% B; Hold 95% B 5 min.

[0109] Flow Rate: 22.5 mL/min

[0110] The product peak was collected based on UV absorption andconcentrated.

[0111] 2. Analytical LCMS Conditions:

[0112] Hewlett Packard 1100 MSD with ChemStation Software

[0113] Column: YMC ODS-AM 2.0 mm×50 mm 5μ column at 23° C.

[0114] Solvent A: Water (0.02% TFA buffer)

[0115] Solvent B: Acetonitrile (0.02% TFA buffer)

[0116] Gradient: Time 0: 5% B; 0.3 min: 5% B; 3.0 min: 90% B; Hold 95% B2 min.

[0117] Flow rate 1.5 mL/min

[0118] Detection: 254 nm DAD; API-ES Scanning Mode Positive 150-700;Fragmentor 70 mV.

What is claimed:
 1. Compounds of formula (I):

wherein: R₁ is hydrogen, C₂-C₆ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆cycloalkyl, or C₁-C₃ perfluoroalkyl, wherein the alkyl and cycloalkylgroups may be optionally substituted with halogen, —CN, C₁-C₆ alkoxy,—OH, —NH₂, or —NO₂; R₂ is hydrogen, or C₁-C₈ alkyl, C₃-C₆ cycloalkyl,—CH₂—C₃-C₆ cycloalkyl, thienyl, CH₂-thienyl, furanyl, CH₂-furanyl,oxazoyl, CH₂-oxazoyl, phenyl, benzyl, CH₂-naphthyl, wherein the alkylgroup and the rings of the cycloalkyl, thienyl, furanyl, oxazoyl,phenyl, benzyl, and napthyl groups may be optionally substituted by from1 to 3 groups selected from halogen, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl,—O—C₁-C₃ perfluoroalkyl, —S—C₁-C₃ perfluoroalkyl, C₁-C₃ alkoxy, —OCHF₂,—CN, —COOH, —CH₂CO₂H, —C(O)CH₃, —CO₂R₆, —C(O)NH₂, —S(O)₂CH₃, —OH, —NH₂,or —NO₂; R₃ is hydrogen, halogen, C₁-C₆ alkyl, C₁-C₃ perfluoroalkyl,C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl, —NH₂, or —NO₂; R₄is C₃-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₆ cycloalkyl,—CH₂—C₃-C₆ cycloalkyl, thienyl, furanyl, oxazoyl, phenyl,benzo[b]furan-2-yl, benzo[b]thien-2-yl, benzo[1,3]dioxol-5-yl, naphthyl,wherein the alkyl groups and the rings of the cycloalkyl, thienyl,furanyl, oxazoyl, phenyl, benzofuranyl, benzothienyl, and naphthylgroups may be optionally substituted by from 1 to 3 groups selected fromhalogen, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl, —O—C₁-C₃ perfluoroalkyl,—S—C₁-C₃ perfluoroalkyl, C₁-C₃ alkoxy, —OCHF₂, —CN, —COOH, CH₂CO₂H,—C(O)CH₃, —C(O)OR₆, —C(O)NH₂, —S(O)₂CH₃, —OH, —NH₂, or —NO₂; R₅ is C₁-C₈alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl, pyridinyl,—CH₂-pyridinyl, thienyl, CH₂-thienyl, furanyl, CH₂-furanyl, oxazoyl,CH₂-oxazoyl, phenyl, benzyl, benzo[b]furan-2-yl, benzo[b]thien-2-yl,benzo[1,3]dioxol-5-yl, naphthyl, CH₂-naphyl, 9H-fluoren-1-yl,9H-fluoren-4-yl, 9H-fluoren-9-yl, 9-fluorenone-1-yl, 9-fluorenone-2-yl,9-fluorenone-4-yl, CH₂-9H-fluoren-9-yl, wherein the alkyl group and therings of the cycloalkyl, pyridinyl, thienyl, furanyl, oxazoyl, phenyl,benzyl, benzofuranyl, benzothienyl, napthyl, fluorenyl, and fluorenonegroups may be optionally substituted by from 1 to 3 groups selected fromhalogen, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, C₁-C₃ perfluoroalkyl, —O—C₁-C₃perfluoroalkyl, —S—C₁-C₃ perfluoroalkyl, C₁-C₃ alkoxy, phenoxy, —OCHF₂,—CN, —COOH, —CH₂CO₂H, —C(O)CH₃, —CO₂R₆, —C(O)NH₂, —S(O)₂CH₃, —OH, —NH₂,or —NO₂, wherein the phenoxy group may be optionally substituted by from1 to 3 groups selected from halogen, C₁-C₃ alkyl, or C₁-C₃perfluoroalkyl; and R₆ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆cycloalkyl, or benzyl; or a pharmaceutically acceptable salt or esterform thereof.
 2. The compound of claim 1 wherein R, —R₃ and R₅-R₆ are asdefined in claim 1, and R₄ is thienyl, furanyl, oxazoyl, phenyl,benzo[b]furan-2-yl, benzo[b]thien-2-yl, benzo[1,3]dioxol-5-yl, ornaphthyl, wherein the rings of the thienyl, furanyl, oxazoyl, phenyl,benzofuranyl, benzothienyl, and napthyl groups may be optionallysubstituted by from 1 to 3 groups selected from halogen, C₁-C₃ alkyl,C₁-C₃ perfluoroalkyl, —O—C₁-C₃ perfluoroalkyl, —S—C₁-C₃ perfluoroalkyl,C₁-C₃ alkoxy, —OCHF₂, —CN, —COOH, —CH₂CO₂H, —C(O)CH₃, —CO₂R₈, —C(O)NH₂,—S(O)₂CH₃, —OH, —NH₂, or —NO₂.
 3. The compound of claim 1 which is[3-(4-chlorobenzoyl)-5-(4-chlorophenyl)-1H-indol-1-yl]acetic acid, or apharmaceutically acceptable salt or ester form thereof.
 4. The compoundof claim 1 which is[3-(Benzo[b]thiophene-2-carbonyl)-5-(4-methylphenyl)-1H-indol-1-yl]-aceticacid, or a pharmaceutically acceptable salt or ester form thereof. 5.The compound of claim 1 which is[3-(4-chlorobenzoyl)-5-(4-methylphenyl)-1H-indol-1-yl]-acetic acid, or apharmaceutically acceptable salt or ester form thereof.
 6. A method ofinhibiting in a mammal plasminogen activator inhibitor type 1,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of a compound of formula (I):

wherein: R₁ is hydrogen, C₂-C₆ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆cycloalkyl, or C₁-C₃ perfluoroalkyl, wherein the alkyl and cycloalkylgroups may be optionally substituted with halogen, —CN, C₁-C₆ alkoxy,—OH, —NH₂, or —NO₂; R₂ is selected from hydrogen, or C₁-C₈ alkyl, C₃-C₆cycloalkyl, —CH₂—C₃-C₆ cycloalkyl, thienyl, CH₂-thienyl, furanyl,CH₂-furanyl, oxazoyl, CH₂-oxazoyl, phenyl, benzyl, CH₂-naphthyl, whereinthe alkyl group and the rings of the cycloalkyl, thienyl, furanyl,oxazoyl, phenyl, benzyl, and napthyl groups may be optionallysubstituted by from 1 to 3 groups selected from halogen, C₁-C₃ alkyl,C₁-C₃ perfluoroalkyl, —O—C₁-C₃ perfluoroalkyl, —S—C₁-C₃ perfluoroalkyl,C₁-C₃ alkoxy, —OCHF₂, —CN, —COOH, —CH₂CO₂H, —C(O)CH₃, —CO₂R₆, —C(O)NH₂,—S(O)₂CH₃, —OH, —NH₂, or —NO₂; R₃ is hydrogen, halogen, C₁-C₆ alkyl,C₁-C₃ perfluoroalkyl, C₁-C₆ alkoxy, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆cycloalkyl, —NH₂, or —NO₂; R₄ is C₃-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl, thienyl, furanyl,oxazoyl, phenyl, benzo[b]furan-2-yl, benzo[b]thien-2-yl,benzo[1,3]dioxol-5-yl, naphthyl, wherein the alkyl group and the ringsof the cycloalkyl, thienyl, furanyl, oxazoyl, phenyl, benzofuranyl,benzothienyl, and napthyl groups may be optionally substituted by from 1to 3 groups selected from halogen, C₁-C₃ alkyl, C₁-C₃ perfluoroalkyl,—O—C₁-C₃ perfluoroalkyl, —S—C₁-C₃ perfluoroalkyl, C₁-C₃ alkoxy, —OCHF₂,—CN, COOH, —CH₂CO₂H, —C(O)CH₃, —C(O)OR₆, —C(O)NH₂, —S(O)—₂CH₃, —OH,—NH₂, or —NO₂; R₅ is C₁-C₈ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆cycloalkyl, pyridinyl, —CH₂-pyridinyl, thienyl, CH₂-thienyl, furanyl,CH₂-furanyl, oxazoyl, CH₂-oxazoyl, phenyl, benzyl, benzo[b]furan-2-yl,benzo[b]thien-2-yl, benzo[1,3]dioxol-5-yl, naphthyl, CH₂-naphyl,9H-fluoren-1-yl, 9H-fluoren-4-yl, 9H-fluoren-9-yl, 9-fluorenone-1-yl,9-fluorenone-2-yl, 9-fluorenone-4-yl, CH₂-9H-fluoren-9-yl, wherein thealkyl group and the rings of the cycloalkyl, pyridinyl, thienyl,furanyl, oxazoyl, phenyl, benzyl, benzofuranyl, benzothienyl, napthyl,fluorenyl, and fluorenone groups may be optionally substituted by from 1to 3 groups selected from halogen, C₁-C₃ alkyl, C₃-C₆ cycloalkyl, C₁-C₃perfluoroalkyl, —O—C₁-C₃ perfluoroalkyl, —S—C₁-C₃ perfluoroalkyl, C₁-C₃alkoxy, phenoxy, —OCHF₂, —CN, —COOH, —CH₂CO₂H, —C(O)CH₃, —CO₂R₆,—C(O)NH—₂, —S(O)₂CH₃, —OH, —NH₂, or —NO₂, wherein the phenoxy groupmaybe optionally substituted by from 1 to 3 groups selected fromhalogen, C₁-C₃ alkyl, or C₁-C₃ perfluoroalkyl; and R₆ is selected fromC₁-C₆ alkyl, C₃-C₆ cycloalkyl, —CH₂—C₃-C₆ cycloalkyl, or benzyl; or apharmaceutically acceptable salt or ester form thereof.
 7. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutical carrier.
 8. A method for treatment of thrombosis orfibrinolytic impairment in a mammal, the method comprising administeringto a mammal in need thereof a pharmaceutically effective amount of acompound of claim
 1. 9. A method of claim 8 wherein the thrombosis orfibrinolytic impairment is associated with formation of atheroscleroticplaques, venous and arterial thrombosis, myocardial ischemia, atrialfibrillation, deep vein thrombosis, coagulation syndromes, pulmonaryfibrosis, cerebral thrombosis, thromboembolic complications of surgeryor peripheral arterial occlusion.
 10. A method for the treatment ofperipheral arterial disease in a mammal, comprising administering to amammal in need thereof a pharmaceutically effective amount of a compoundof claim
 1. 11. A method for the treatment of stroke associated with orresulting from artrial fibrillation in a mammal, comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of claim
 1. 12. A method for the treatment of deepvein thrombosis in a mammal, comprising administering to a mammal inneed thereof a pharmaceutically effective amount of a compound ofclaim
 1. 13. A method for the treatment of myocardial ischemia in amammal, comprising administering to a mammal in need thereof apharmaceutically effective amount of a compound of claim
 1. 14. A methodfor the treatment of a cardiovascular disease caused by noninsulindependent diabetes mellitus in a mammal, comprising administering to amammal in need thereof a pharmaceutically effective amount of a compoundof claim
 1. 15. A method for the treatment of the formation ofatherosclerotic plaques in a mammal, comprising administering to amammal in need thereof a pharmaceutically effective amount of a compoundof claim
 1. 16. A method for the treatment of chronic obstructivepulmonary disease in a mammal, comprising administering to a mammal inneed thereof a pharmaceutically effective amount of a compound ofclaim
 1. 17. A method for the treatment of renal fibrosis in a mammal,comprising administering to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of claim
 1. 18. A method for thetreatment of polycystic ovary syndrome in a mammal, comprisingadministering to a mammal in need thereof a pharmaceutically effectiveamount of a compound of claim
 1. 19. A method for the treatment ofAlzheimer's disease in a mammal, comprising administering to a mammal inneed thereof a pharmaceutically effective amount of a compound ofclaim
 1. 20. A method for the treatment of cancer in a mammal,comprising administering to a mammal in need thereof a pharmaceuticallyeffective amount of a compound of claim 1.